PROJECT SUMMARY With an incidence of one in 700-1000 live births worldwide, Down Syndrome (DS), or trisomy of human chromosome 21 (Hsa21), is the most common chromosomal abnormality. While DS is most often recognized for intellectual disability, congenital malformations, and dysmorphic features, it is also associated with seriously increased rates and severity of respiratory infection. Indeed, infectious respiratory disease in those with DS accounts for 54% of hospital admissions and more deaths than any other medical condition. Children with DS have a 62-fold higher rate of pneumonia than children without DS(1). During the influenza A (H1N1) pandemic in 2009, 23% of hospitalized patients with DS died vs. only 0.1% of those without DS. Collectively, these data point to an urgent need to understand how the condition of trisomy 21 contributes to respiratory infectious disease and to identify potential therapeutic targets. Currently, infectious respiratory disease in DS is commonly attributed to congenital abnormalities of the nasopharynx and upper and lower airways. However, our preliminary data support the novel hypothesis that immune cell dysfunction is a primary driver of increased incidence and severity of infectious respiratory disease in DS. Our data show that the trisomic Dp16 mouse lung has higher levels of interferons and the immunosuppressive cytokine Interleukin (IL)-10. These changes closely mimic the dysregulated cytokine response in the human lung that has long been observed following influenza infection, and is a state linked to increased susceptibility to lethal bacterial pneumonia. Importantly, Dp16 mice are trisomic for the Hsa21-encoded interferon receptors and interferon-responsive genes. Based on these data, we hypothesize that the constitutive activation state of interferon signaling and IL-10 signaling in the DS lung drives immune suppression and predisposes individuals with DS to S. pneumoniae pneumonia. This state phenocopies the increased susceptibility and severity of S. pneumoniae pneumonia that is observed in non-DS individuals after a course of viral infection. The high morbidity and mortality associated with infectious respiratory disease is a seriously neglected area of medical need for people with DS. In addition, chronic lung disease is increasingly associated with cognitive deficit. Conceptualizing DS as a post-viral state of susceptibility to bacterial infection challenges the existing paradigm of congenital abnormality. Proposing to understand the mechanisms involved in immune suppression and to identify therapeutic targets and agents to ameliorate frequency and severity of disease, while high risk, would, if successful, provide a high payoff in the increased health and longevity of people with and without DS.